Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas with weak toxicological effects on adrenal glands

A Tanaka; T Terasawa; H Hagihara; N Ishibe; M Sawada; Y Sakuma; M Hashimoto; H Takasugi; H Tanaka

doi:10.1021/jm980399q

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas with weak toxicological effects on adrenal glands

J Med Chem. 1998 Oct 22;41(22):4408-20. doi: 10.1021/jm980399q.

Authors

A Tanaka¹, T Terasawa, H Hagihara, N Ishibe, M Sawada, Y Sakuma, M Hashimoto, H Takasugi, H Tanaka

Affiliation

¹ Medicinal Chemistry Research Laboratories, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Company Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.

PMID: 9784116
DOI: 10.1021/jm980399q

Abstract

A series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.

MeSH terms

Acetylation
Adrenal Glands / drug effects
Animals
Anticholesteremic Agents / chemical synthesis*
Anticholesteremic Agents / chemistry
Anticholesteremic Agents / pharmacology
Anticholesteremic Agents / toxicity
Cholesterol, Dietary / administration & dosage
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / toxicity
In Vitro Techniques
Intestines / enzymology
Lipoproteins, LDL / metabolism
Macrophages, Peritoneal / drug effects
Macrophages, Peritoneal / metabolism
Mice
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Pyridines / toxicity
Rabbits
Rats
Sterol O-Acyltransferase / antagonists & inhibitors*
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / chemistry
Urea / pharmacology
Urea / toxicity

Substances

Anticholesteremic Agents
Cholesterol, Dietary
Enzyme Inhibitors
FR 186485
Lipoproteins, LDL
Pyridines
FR 190809
Urea
Sterol O-Acyltransferase